The proposal has the long-term goal of determining the factors that cause sex differences in neural systems. For almost 50 years the central concept of sexual differentiation of the brain has held that all sex differences in brain and behavior result from the perinatal actions of gonadal steroid hormones. Recent research on the neural circuit for song in zebra finches conflicts with this classic dogma, and indicates that genes encoded on the sex chromosomes, which are differently expressed in male and female brain cells, acts within those cells to cause sexual differentiation. The proposed experiments will provide further information about this important model system. (1) Experiments will evaluate whether the trkB gene; which is present in two copies in the male genome but only one copy in the female genome, is responsible for male-specific growth and differentiation of specific brain regions. Other genes present in different copy numbers in the genome of males and females will be examined for sex differences in expression. (2) Genes that are present only in the female genome will be studied in brain to determine when and where the genes are expressed, and if the expression pattern is different from closely related genes present in the male genome. Novel female-specific genes will be identified, cloned, and their expression studied. (3) The hypothesis will be tested that males have higher levels of estrogen synthesis in the brain just prior to the earliest known sex differences in development of the vocal control system. (4) The role of androgens in early neurogenesis and neural migration will be evaluated as a potential mechanism of male-specific growth and differentiation. (5) The interrelated roles of sex steroid hormones and protein trophic factors will be evaluated prior to the earliest known sex differences in development. The proposed experiments will shed light on genetic and hormonal mechanisms of brain sexual differentiation, and may provide new understanding of sex differences in brain development and disease.